Methods for producing pyrimidine compounds

ABSTRACT

A method for producing 2-amino-4,6-dimethoxypyrimidine, wherein 2-amino-5-chloro-4,6-dimethoxypyrimidine produced by reacting heptachloropropane or hexachloropropene and guanidine with methanol in the presence of a base, or by reacting 2-amino-4,5,6-trichloropyrimidine with methanol in the presence of a base, is used; and a method for producing 2-amino-4,6-dimethoxypyrimidine, characterized by reacting hexachloropropane or pentachloropropene and guanidine with methanol in the presence of a base.

TECHNICAL FIELD

The present invention relates to methods for producing2-amino-4,6-dimethoxypyrimidine useful as an intermediate for drugs andpesticides, particularly as an intermediate for herbicides, its startingmaterial 2-amino-5-chloro-4,6-dimethoxypyrimidine and its intermediate2-amino-4,5-dichloro-6-methoxypyrimidine.

BACKGROUND ART

2-Amino-4,6-dimethoxypyrimidine and its derivatives are a group ofcompounds which are useful as intermediates for various fine chemicalssuch as biologically active substances, like drugs and pesticides aswell as important intermediates for sulfonylurea herbicides described inJP-A-59-122488, JP-A-61-210084 and JP-A-60-208977.

2-Amino-4,5-dichloro-6-methoxypyrimidine is useful, for example, forproducing phenylaminopyrimidine compounds described in JP-A-60-51177 andJP-A-61-15877.

As a method for producing 2-amino-4,6-dimethoxypyrimidine, many methodshave been known. For example, JP-B-1-211411 discloses a productionmethod by reacting bisimidate obtained from malononitrile withcyanogenchloride. And JP-A-64-16770 discloses a method for producing2-amino-4,6-dimethoxypyrimidine by reacting2-amino-4,6-dihydroxypyrimidine with phosphorous oxychloride in thepresence of an organic base to prepare 2-amino-4,6-dichloropyrimidine(J. Amer. Chem. Soc., vol. 73, page 3011 (1951)), followed bymethoxylation with a metal hydroxide and methanol.

On the other hand, as a method for producing2-amino-5-chloro-4,6-dimethoxypyrimidine, a method to chlorinate2-amino-4,6-dimethoxypyrimidine has been known as described in J. Chem.Soc. Perkin Trans. 1, page 375 (1975).

However, with the conventional methods, various types of by-products aregenerated with large quantities, and improvement is therefore required.And, 2-amino-4,5-dichloro-6-methoxypyrimidine and methods for itsproduction have not been known at all.

DISCLOSURE OF THE INVENTION

The present inventors have conducted extensive studies to overcome theabove problems, and the present invention has been accomplished. Namely,the present invention provides a method for producing2-amino-4,6-dimethoxypyrimidine (hereinafter referred to as compound(I)), characterized by reacting 2-amino-5-chloro-4,6-dimethoxypyrimidine(hereinafter referred to as compound (II)) with a hydrogen donor using ametal catalyst selected from nickel catalyst, palladium catalyst andplatinum catalyst, in the presence of a base if necessary (hereinafterreferred to as production method A), a method for producing compound(I), using compound (II) produced by reacting1,1,1,2,2,3,3-heptachloropropane, 1,1,1,2,3,3,3-heptachloropropane orhexachloropropene with guanidine or its salt, in the presence of analkali metal hydroxide, an alkaline earth metal hydroxide, an alkalimetal methoxide or an alkaline earth metal methoxide (hereinafterreferred to as production method A1), a method for producing compound(I), using compound (II) produced by reacting2-amino-4,5-dichloro-6-methoxypyrimidine (hereinafter referred to ascompound (III)) with methanol, in the presence of an alkali metalhydroxide, an alkaline earth metal hydroxide, an alkali metal methoxideor an alkaline earth metal methoxide (hereinafter referred to asproduction method A2), a method for producing compound (II), usingcompound (III) produced by reacting 2-amino-4,5,6-trichloropyrimidine(hereinafter referred to as compound (IV)) with methanol, in thepresence of an alkali metal carbonate, an alkali metalhydrogencarbonate, an alkaline earth metal carbonate or an alkalineearth metal hydrogencarbonate (hereinafter referred to as productionmethod A3), a method for producing compound (I), using compound (II)produced by reacting compound (IV), with methanol, in the presence of analkali metal hydroxide, an alkaline earth metal hydroxide, an alkalimetal methoxide or an alkaline earth metal methoxide (hereinafterreferred to as production method A4), a method for producing compound(I), characterized by reacting 1,1,1,3,3,3-hexachloropropane or1,1,3,3,3-pentachloropropene with guanidine or its salt, in the presenceof an alkali metal hydroxide, an alkaline earth metal hydroxide, analkali metal methoxide or an alkaline earth metal methoxide (hereinafterreferred to as production method B), a method for producing compound(II), characterized by reacting 1,1,1,2,2,3,3-heptachloropropane,1,1,1,2,3,3,3-heptachloropropane or hexachloropropene with guanidine orits salt, in the presence of an alkali metal hydroxide, an alkalineearth metal hydroxide, an alkali metal methoxide or an alkaline earthmetal methoxide (hereinafter referred to as production method C), amethod for producing compound (II), characterized by reacting compound(III) with methanol, in the presence of an alkali metal hydroxide, analkaline earth metal hydroxide, an alkali metal methoxide or an alkalineearth metal methoxide (hereinafter referred to as production method D),a method for producing compound (II), characterized by reacting compound(IV) with methanol, in the presence of an alkali metal hydroxide, analkaline earth metal hydroxide, an alkali metal methoxide or an alkalineearth metal methoxide (hereinafter referred to as production method E),a method for producing compound (II), characterized by reacting compound(IV) with methanol, in the presence of an alkali metal carbonate, analkali metal hydrogencarbonate, an alkaline earth metal carbonate or analkaline earth metal hydrogencarbonate (hereinafter referred to asproduction method F). And compound III is a novel compound.

BEST MODE FOR CARRYING OUT THE INVENTION

Hydrogenolysis in production method A can be conducted by using nickelcatalyst, palladium catalyst or platinum catalyst. And, the reaction canbe conducted in the coexistence of an organic base or an inorganic baseas a hydrochloric acid scavenger.

As the organic base or the inorganic base, ammonia, triethylamine,pyridine, ammonium formate, sodium formate, potassium formate, sodiumacetate, potassium acetate, sodium hydroxide, potassium hydroxide,sodium carbonate and potassium carbonate are preferred. The amount ofthe organic base or the inorganic base is preferably from 1 to 10 mol,more preferably from 1 mol to small excess, per mol of2-amino-5-chloro-4,6-dimethoxypyrimidine.

As the hydrogen donor, hydrogen gas, sodium borohydride and sodiumformate are preferred, and hydrogen gas is particularly preferred.

The reaction pressure is preferably from reduced pressure to 100 atm,more preferably from atmospheric pressure to 10 atm.

The reaction temperature is preferably from 0 to 300° C., morepreferably from 20 to 150° C.

The reaction time is preferably from one minute to 50 hours, morepreferably from 30 minutes to 10 hours.

The solvent to be used for the present reaction is not particularlylimited as long as it is inert to the reaction. It includes, forexample, water, ethers such as tetrahydrofuran, diethyl ether,diethylene glycol diethyl ether and 1,4-dioxane, aliphatic hydrocarbonssuch as hexane, heptane, octane, nonane and decane, aromatichydrocarbons such as benzene, toluene, xylene, andtetrahydronaphthaline, alcohols such as methanol, ethanol, propanol andethylene glycol, cellosolves such as methoxyethanol and ethoxyethanol,fatty acids such as formic acid, acetic acid and propionic acid, andtheir mixed solvents.

As a treatment method of reaction solution, the reaction products may bepurified or isolated by e.g. extraction, distillation,recrystallization, or chromatography separation, if necessary, after thesolvent is removed by distillation.

1,1,1,3,3,3-Hexachloropropane or 1,1,3,3,3-pentachloropropene to be usedas a starting material in production method B can be easily produced byknown methods. For example, 1,1,1,3,3,3-hexachloropropane can beproduced by the method disclosed in J. Mol. Catal. vol. 77, page 51(1992), and 1,1,3,3,3-pentachloropropene can be easily produced by themethod disclosed in Chem. Ber. vol. 100, page 3716 (1967).

As the alkali metal hydroxide or the alkaline earth metal hydroxide,potassium hydroxide, sodium hydroxide, barium hydroxide, magnesiumhydroxide and calcium hydroxide are preferred, and sodium hydroxide isparticularly preferred.

As the alkali metal methoxide or the alkaline earth metal methoxide,lithium methoxide, sodium methoxide, potassium methoxide, magnesiummethoxide, calcium methoxide, barium methoxide and strontium methoxideare preferred, and sodium methoxide is particularly preferred. And thesemay be simple substances or in the form of methanol solutions.

The amount of the methoxide is preferably from 2 to 15 mol, morepreferably from 4 to 10 mol, per mol of 1,1,1,3,3,3-hexachloropropane or1,1,3,3,3-pentachloropropene.

The reaction temperature is preferably from -70 to 200° C., morepreferably from 0 to 100° C.

The solvent is not particularly limited as long as it is inert to thereaction. It includes, for example, water, ethers such astetrahydrofuran, diethyl ether diethylene glycol dimethyl ether and1,4-dioxane, aliphatic hydrocarbons such as hexane, heptane, octane,nonane and decane, aromatic hydrocarbons such as benzene, toluene,xylene, chlorobenzene, dichlorobenzene and tetrahydronaphthalene,nitriles such as acetonitrile, ketones such as acetone and methylisobutylketone, polar solvents such as N,N-dimethylformamide,N,N-dimethylacetamide, dimethyl sulfoxide and1,3-dimethyl-2-imidazolidinone, methanol, and their mixed solvents.

The present reaction can be conducted either under atmospheric pressureor under elevated pressure.

In the present invention, compound (I) can be obtained by reacting aguanidine salt with a methoxide in the presence of a solvent to liberateguanidine, then adding 1,1,1,3,3,3-hexachloropropane or1,1,3,3,3-pentachloropropene thereto, or by reacting a mixture of aguanidine salt and 1,1,1,3,3,3-hexachloropropane or1,1,3,3,3-pentachloropropene with a methoxide added in the presence of asolvent, then adding water and extracting the reaction products with anorganic solvent, followed by crystallizing and washing.

As the alkali metal hydroxide or the alkaline earth metal hydroxide tobe used in the production method C, potassium hydroxide, sodiumhydroxide, barium hydroxide, magnesium hydroxide and calcium hydroxideare preferred, and sodium hydroxide is particularly preferred. As thealkali metal methoxide or the alkaline earth metal methoxide, lithiummethoxide, sodium methoxide, potassium methoxide, magnesium methoxide,calcium methoxide, barium methoxide and strontium methoxide, bariummethoxide and strontium methoxide are preferred, and sodium methoxide isparticularly preferred. They can be used either as simple substances orin the form of methanol solutions.

The alkali metal methoxide or the alkaline earth metal methoxide can beproduced by adding sodium hydride, potassium hydride, lithium hydride,metal sodium, metal potassium, metal lithium, butyl lithium or lithiumdiisopropylamide into methanol.

The amount of methoxide is preferably from 2 to 10 mol, more preferablyfrom 4.0 to 7.0 mol, per mol of 1,1,1,2,2,3,3-heptachloropropane,1,1,1,2,3,3,3-heptachloropropane or hexachloropropene.

As the guanidine salt, not only inorganic acid salts such ashydrochloride, nitrate, sulfate and carbonate, but organic acid saltscan be used as well. Its amount is usually preferably from 0.5 to 10mol, more preferably from 0.8 to 2 mol, per mol of heptachloropropane orhexachloropropene.

The reaction temperature, is preferably from -10 to 200° C., morepreferably from 20 to 150° C.

The solvent is not particularly limited as long as it is inert to thereaction. It includes, for example, water, ethers such astetrahydrofuran, diethyl ether diethylene glycol dimethyl ether and1,4-dioxane, aliphatic hydrocarbons such as hexane, heptane, octane,nonane and decane, aromatic hydrocarbons such as benzene, toluene,xylene, chlorobenzene, dichlorobenzene and tetrahydronaphthalene,nitrites such as acetonitrile, ketones such as acetone and methylisobutylketone, polar solvents such as N,N-dimethylformamide,N,N-dimethylacetamide, dimethyl sulfoxide and1,3-dimethyl-2-imidazolidinone, methanol, and their mixed solvents.

The present reaction can be conducted either under atmospheric pressureor under elevated pressure.

In the present invention, compound (II) can be obtained in good yield byreacting a guanidine salt with a methoxide in the presence of a solventto liberate guanidine, then adding 1,1,1,2,2,3,3-heptachloropropane,1,1,1,2,3,3,3-heptachloropropane or hexachloropropene thereto, or byreacting a guanidine salt and 1,1,1,2,2,3,3-heptachloropropane,1,1,1,2,3,3,3-heptachloropropane or hexachloropropene with a methoxidein the presence of a solvent, then adding water and extracting thereaction products with an organic solvent, followed by crystallizing andwashing.

As the alkali metal hydroxide, the alkaline earth metal hydroxide, thealkali metal methoxide or the alkaline earth metal methoxide to be usedin production method D, sodium methoxide, potassium hydroxide, sodiumhydroxide, barium hydroxide, magnesium hydroxide and calcium hydroxideare preferred, and sodium hydroxide is particularly preferred in view ofreactivity and economy. And, they can be used as a mixture of at leasttwo bases.

The amount of base is preferably from none to 10 mol, more preferablyfrom 1 to 3 mol, per mol of compound (III).

The reaction pressure is preferably from reduced pressure to 100 atm,more preferably from atmospheric pressure to 10 atm.

The reaction temperature is preferably from 0 to 300° C., morepreferably from 20 to 150° C.

The reaction time is preferably from 10 minutes to 50 hours, morepreferably from 30 minutes to 10 hours.

The solvent is not particularly limited as long as it is inert to thereaction. It includes, for example, water, ethers such astetrahydrofuran, diethyl ether, diethylene glycol dimethyl ether and1,4-dioxane, aliphatic hydrocarbons such as hexane, heptane, octane,nonane, and decane, aromatic hydrocarbons such as benzene, toluene,xylene and tetrahydronaphthalene, methanol and their mixed solvents.

As a treatment method of the reaction solution, the solvent is removedby distillation, if necessary, and then, water is added to precipitatecrystals followed by washing and filtration to obtain the desiredproduct. Or, after the solvent is removed,2-amino-5-chloro-4,6-dimethoxypyrimidine can be purified or isolated byextraction, recrystallization and chromatography separation of thereaction product.

As the alkali metal hydroxide, the alkaline earth metal hydroxide, thealkali metal methoxide or the alkaline earth metal methoxide to be usedin production method E, sodium methoxide, potassium hydroxide, sodiumhydroxide, barium hydroxide, magnesium hydroxide and calcium hydroxideare preferred, and sodium hydroxide is particularly preferred in view ofreactivity and economy. And, they can be used as a mixture of at leasttwo bases.

The amount of base is preferably from none to 10 mol, more preferablyfrom small excess to 2 mol, per mol of compound (IV).

The reaction pressure is preferably from reduced pressure to 100 atm,more preferably from atmospheric pressure to 10 atm.

The reaction temperature is preferably from 0 to 300° C., morepreferably from 20° C. to 150° C.

The reaction time is preferably from 10 minutes to 50 hours, morepreferably from 30 minutes to 10 hours.

The solvent is not particularly limited as long as it is inert to thereaction, it includes, for example, water, ethers such astetrahydrofuran, diethyl ether, diethylene glycol diethyl ether and1,4-dioxane, aliphatic hydrocarbons such as hexane, heptane, octane,nonane and decane, aromatic hydrocarbons such as benzene, toluene;xylene and tetrahydronaphthaline, methanol and their mixed solvents.

As a treatment method of the reaction solution, the solvent is removedby distillation if necessary, and then the reaction product is subjectedto e.g. extraction, recrystallization or chromatography separation topurify or isolate the compound (I). Compound (IV) which is a startingmaterial of the present invention, can be produced by known methods [forexample, J. Amer. Chem. Soc., vol. 72, page 4271 (1950)].

As the alkali metal carbonate or the alkali metal hydrogencarbonate tobe used in the production method F, sodium hydrogencarbonate, potassiumhydrogencarbonate, sodium carbonate and potassium carbonate arepreferred, and sodium carbonate is particularly preferred in view ofreactivity and economy. As the alkaline earth metal carbonate or thealkaline earth metal hydrogencarbonate, magnesium carbonate, calciumcarbonate, barium carbonate, magnesium hydrogencarbonate and calciumhydrogencarbonate are preferred. It is possible to use a mixture of atleast two bases.

The conditions of production method F are in accordance with conditionsof production method E.

These production methods may be used as combined as production methodsA1, A2, A3 and A4.

EXAMPLES

Now, the present invention will be described in detail with reference toExamples. However, the present invention is not restricted thereto.

Production Method A Example A-1

3.03 g (16 mmol) of compound (II), 0.5 g of active carbon-supported 10%palladium [product of NE Chemcat (water content 50%)], 9.8 g ofpotassium acetate and 300 g of acetic acid were put into a reactionflask substituted by nitrogen, hydrogen gas was supplied underatmospheric pressure, and reaction was conducted at a temperature of100° C. for 6 hours. The disappearance of2-amino-5-chloro-4,6-dimethoxypyrimidine was confirmed by liquidchromatography, acetic acid was distilled off from the reaction mixture,20 g of methylisobutylketone was added thereto, followed by washing withwater. The organic layer was dried over anhydrous sodium sulfate, andthe solvent was distilled off to obtain 2.38 g (15.4 mmol) (yield 96%)of compound (I).

Example A-2

3.03 g (16 mmol) of compound (II) and 0.5 g of active carbon-supported10% palladium [product of NE Chemcat (water content 50%)], 9.8 g ofpotassium acetate and 300 g of acetic acid were put into a reactionflask substituted by nitrogen, and stirred well at a temperature of 25°C. into which hydrogen gas was supplied under atmospheric pressure, andreaction was conducted for 24 hours. The production of 31% of compound(I) was confirmed by liquid chromatography.

Example A-3

3.03 g (16 mmol) of compound (II), 0.5 g of active carbon-supported 10%palladium [product of NE Chemcat (water content 50%)], 9.8 g ofpotassium acetate and 300 g of methoxy ethanol were put into a reactionflask substituted by nitrogen, hydrogen gas was supplied underatmospheric pressure and reaction was conducted at a temperature of 120°C. for 24 hours. The production of 75% of compound (I) was confirmed byliquid chromatography.

Production Method B

1.00 g (10.5 mmol) of guanidine hydrochloride was added to a mixture of3.58 g (63.0 mmol) of 95% sodium methoxide and 10.0 g of diethyleneglycol dimethyl ether, and the reaction was conducted at a temperatureof 60° C. for one hour. 2.25 g (10.5 mmol) of1,1,3,3,3-pentachloropropene was dropwise added thereto at a temperatureof at highest 10° C., and the reaction was conducted for one hour. Then,20 g of methylisobutylketone and 20 g of water were added, and theorganic layer was separated. The organic layer was washed with water,and dried over anhydrous sodium sulfate, and the solvent was distilledoff, whereupon precipitated crystals were washed with heptane, to obtain0.34 g (yield 17%) of compound (I).

Production Method C Example C-1

14.1 g (73.3 mmol) of 28% sodium methoxide (methanol solution) wasdropwise added to a mixture of 1.00 g (10.5 mmol) of guanidinehydrochloride, 2.99 g (10.5 mmol) of 1,1,1,2,2,3,3-heptachloropropaneand 3.0 g of methanol over a period of one hour under reflux. Thereaction was conducted further for one hour, then methanol was distilledoff, 20 g of methylisobutylketone and 20 g of water were added thereto,and the organic layer was separated. The organic layer was dried overanhydrous sodium sulfate, the solvent was distilled off and precipitatedcrystals were washed with heptane to obtain 0.44 g (yield 22%) ofcompound (II).

Example C-2

14.1 g (73.3 mmol) of 28% sodium methoxide (methanol solution) wasdropwise added to a mixture of 1.00 g (10.5 mmol) of guanidinehydrochloride, 2.99 g (10.5 mmol) of 1,1,1,2,3,3,3-heptachloropropaneand 3.0 g of methanol under reflux over a period of one hour. Thereaction was conducted further for one hour, the methanol was distilledoff, 20 g of methylisobutylketone and 20 g of water were added, and theorganic layer was separated. The organic layer was dried over anhydroussodium sulfate, the solvent was distilled off and precipitated crystalswere washed with heptane to obtain 0.50 g (yield 25%) of compound (II).

Example C-3

12.1 g (62.8 mmol) of 28% sodium methoxide (methanol solution) wasdropwise added to a mixture of 1.00 g (10.5 mmol) of guanidinehydrochloride, 2.60 g (10.5 mmol) of hexachloropropene and 3.0 g ofmethanol over a period of one hour under reflux. The reaction wasconducted further for one hour, the methanol was distilled off, 20 g ofmethylisobutylketone and 20 g of water were added, and the organic layerwas separated. The organic layer was dried over anhydrous sodiumsulfate, the solvent was distilled off and precipitated crystals werewashed with heptane to obtain 0.60 g (yield 30%) of compound (II).

Example C-4

3.00 g (31.4 mmol) of guanidine hydrochloride was added to 6.06 g (31.4mmol) of 28% sodium methoxide (methanol solution), then 2.60 g (10.5mmol) of hexachloropropene was dropwise added thereto over a period ofone hour under reflux. One hour later, 10.1 g (52.3 mmol) of 28% sodiummethoxide (methanol solution) was dropwise added thereto over a periodof one hour. The reaction was conducted for one hour and then methanolwas distilled off, 20 g of methylisobutylketone and 20 g of water wereadded, and the organic layer was separated. The organic layer was driedover anhydrous sodium sulfate, the solvent was distilled off andprecipitated crystals were washed with heptane to obtain 0.64 g (yield32%) of compound (II).

Example C-5

6.02 g (63.0 mmol) of guanidine hydrochloride was added to 12.2 g (63.0mmol) of 28% sodium methoxide (methanol solution), then 2.60 g (10.5mmol) of hexachloropropene was dropwise added thereto over a period ofone hour under reflux. The reaction was conducted further for one hour,then methanol was distilled off, 20 g of methylisobutylketone and 20 gof water were added, and the organic layer was separated. The organiclayer was dried over anhydrous sodium sulfate, the solvent was distilledoff and precipitated crystals were washed with heptane to obtain 0.66 g(yield 33%) of compound (II).

Example C-6

A solution containing 2.52 g (63.0 mmol) of sodium hydroxide dissolvedin 12.6 g of methanol was dropwise added into a mixture of 1.00 g (10.5mmol) of guanidine hydrochloride, 2.60 g (10.5 mmol) ofhexachloropropene and 3.0 g of methanol over a period of one hour underreflux. The reaction was conducted for one hour, methanol was distilledoff, 20 g of methylisobutylketone and 20 g of water were added, and theorganic layer was separated. The organic layer was dried over anhydroussodium sulfate, the solvent was distilled off, whereupon precipitatedcrystals were washed with heptane to obtain 0.56 g (yield 28%) ofcompound (II).

Example C-7

1.20 g (12.6 mmol) of guanidine hydrochloride was added to 3.70 g of 95%sodium methoxide and 10.0 g of diethylene glycol dimethyl ether,followed by heating at a temperature of 60° C. for one hour. After thereaction solution was cooled to -10° C., the mixed solution of 2.60 g ofhexachloropropene and 5 g of diethylene glycol dimethyl ether wasdropwise added thereto at a temperature of at highest 0° C., and thereaction was conducted for one hour. It was confirmed that in thisreaction solution, 0.80 g (yield 40%) of the desired compound (II) inthe internal standardization amount exists.

Example C-8

1.20 g (12.6 mmol) of guanidine hydrochloride was added to 3.70 g of 95%sodium methoxide and 20.0 g of diethylene glycol dimethyl ether,followed by heating at a temperature of 60° C. for one hour, and then 5g of diethylene glycol dimethyl ether was distilled off. The reactionsolution was cooled to -10° C., then a mixed solution of 2.60 g ofhexachloropropene and 5 g of diethylene glycol dimethyl ether wasdropwise added thereto at a temperature of at highest 0° C., and thereaction was conducted for one hour. It was confirmed that in thisreaction solution, 1.00 g (yield 50%) of the desired compound (II) inthe internal standardization amount exists.

Example C-9

1.20 g (12.6 mmol) of guanidine hydrochloride was added to 3.70 g (65.1mmol) of 95% sodium methoxide and 10.0 g of 1-methyl-2-pyrrolidinone,followed by heating at a temperature of 60° C. for one hour. Thereaction solution was cooled to -10° C., then a mixed solution of 2.60 g(10.5 mmol) of hexachloropropene and 5 g of 1-methyl-2-pyrrolidinone,was dropwise added thereto at a temperature of at highest 0° C, and thereaction was conducted for one hour. It was confirmed that in thisreaction solution, 0.80 g (yield 40%) of the desired compound (II) inthe internal standardization amount exists.

Example C-10

1.20 g (12.6 mmol) of guanidine hydrochloride was dissolved in 10.0 g ofmethanol, and 2.63 g (65.1 mmol) of 99% sodium hydroxide was addedthereto, followed by reaction for one hour. Methanol was distilled offat a temperature of 40° C., 20.0 g of diethylene glycol dimethyl etherwas added thereto, among which 5.0 g of diethylene glycol dimethyl etherwas distilled off. Then the mixture was cooled to -10° C. and 2.60 g(10.5 mmol) of hexachloropropene was dropwise added over a period of 30minutes, and the reaction was conducted for one hour. It was confirmedthat in this reaction solution, 0.40 g (yield 20%) of the desiredcompound (II) in the internal standardization amount exists.

Example C-11

2.63 g (65.1 mmol) of 99% sodium hydroxide was added to a mixture of1.00 g (10.5 mmol) of guanidine hydrochloride, 2.60 g (10.5 mmol) ofhexachloropropene and 10.0 g of methanol at a temperature of 50° C. overa period of 30 minutes. After the reaction was conducted for one hour,methanol was distilled off, 20 g of toluene and 20 g of water wereadded, and the organic layer was separated. The organic layer was driedover anhydrous sodium sulfate, the solvent was distilled off andprecipitated crystals were washed with heptane to obtain 0.16 g (yield8%) of compound (II).

Production Method D Example D-1

A mixture of 1.00 g (5.15 mmol) of compound (III), 1.98 g (10.3 mmol) of28% sodium methoxide (methanol solution) and 6 g of methanol wasrefluxed for three hours. After the reaction, methanol was distilled offand 10 g of water was added to precipitate crystals. The crystals weresubjected to filtration, washed with water and dried to obtain 0.88 g(yield 90%) of compound (II).

Example D-2

A mixture of 1.00 g (5.15 mmol) of compound (III), 0.42 g (10.3 mmol) of28% sodium hydroxide and 9 g of methanol was refluxed for three hours.After the reaction, methanol was distilled off and 10 g of water wasadded to precipitate crystals. The crystals were subjected tofiltration, washed with water and dried to obtain 0.93 g (yield 95%) ofcompound (II).

Production Method E Example E-1

3.97 g (20 mmol) of compound (IV), 2.40 g (60 mmol) of sodium hydroxideand 40 ml of methanol were refluxed under heating for two hours. Afterthe reaction, methanol was distilled off, 50 g of water was added,extraction with 50 g of methylisobutylketone was carried out, theorganic layer was dried over anhydrous sodium sulfate and the solventwas distilled off to obtain 3.60 g (19 mmol) (yield 95%) of compound(II).

Example E-2

3.97 g (20 mmol) of compound (IV), 1.60 g (40 mmol) of sodium hydroxideand 40 g of methanol were charged into an autoclave and heated at atemperature of 120° C. for three hours. The internal pressure was 4.2kg/cm². After cooling, the reaction solution was put into an eggplanttype flask, methanol was distilled off under reduced pressure, 50 g ofwater was added thereto, and extraction with 100 g of ethyl acetate wascarried out. After the organic layer was washed with a sodium hydroxideaqueous solution and washed with water then dried over anhydrous sodiumsulfate, the solvent was distilled off to obtain 3.41 g (18 mmol) (yield90%) of compound (II). Besides, 6.5% of compound (III) was produced.

Example E-3

3.24 g (60 mmol) of sodium methoxide was added to 3.97 g (20 mmol) ofcompound (IV) and 50 ml of methanol under stirring at room temperature,followed by stirring at room temperature for one hour. After thereaction, methanol was distilled off, 50 g of water was added,extraction with 20 g of methylisobutylketone was carried out. Theorganic layer was dried over anhydrous sodium sulfate, and the solventwas distilled off to obtain 3.52 g (18.6 mmol) (yield 93%) of compound(II).

Example E-4

3.97 g (20 mmol) of compound (IV), 3.37 g (60 mmol) of potassiumhydroxide and 40 ml of methanol were refluxed under heating for twohours. After the reaction, methanol was distilled off, 50 g of water wasadded, extraction with 20 g of methylisobutylketone was carried out, theorganic layer was dried over anhydrous sodium sulfate, and the solventwas distilled off to obtain 3.60 g (19 mmol) (yield 95%) of compound(II).

Example E-5

3.97 g (20 mmol) of compound (IV), 1.60 g (40 mmol) of barium hydroxideoctahydrate and 40 g of methanol were charged into an autoclave andheated at a temperature of 120° C. for three hours. The internalpressure was 4.2 kg/cm². After cooling, the reaction solution was putinto an eggplant type flask, methanol was distilled off under reducedpressure, 50 g of water was added thereto, followed by acidificationwith acetic acid, and extraction with 100 g of methylisobutylketone wascarried out. The organic layer was washed with a sodium hydroxideaqueous solution and washed with water then dried over anhydrous sodiumsulfate, the solvent was distilled off to obtain 3.41 g (18 mmol) (yield90%) of compound (II). Besides, 6.5% of compound (III) was produced.

Production Method F Example F-1

3.97 g (20 mmol) of compound (IV), 3.17 g (30 mmol) of sodium carbonateand 40 ml of methanol were refluxed under heating for three hours. Thereaction mixture was evaporate to dryness under reduced pressure, 50 mlof water was added thereto followed by stirring well, and crystals weresubjected to filtration. Then, the crystals were washed with toluene anddried to obtain 3.61 g (yield 93%) of compound (III). Melting point:198.3° C.-203.3° C.

¹ H-NMR δ (ppm) [DMSO-d₆, δ]:3.95 (3H,s), 7.20 (2H,bs)

Example F-2

3.97 g (20 mmol) of compound (IV), 1.60 g (40 mmol) of potassiumcarbonate and 40 g of methanol were charged into an autoclave and heatedat a temperature of 100° C. for two hours. After cooling, the sametreatment as in Example 1 was conducted to obtain 3.00 g of crudecompound (III). As a result of analysis, it was confirmed that theproduct contained 80% of compound (III) and 20% of compound (II) (liquidchromatography relative area).

Example F-3

3.97 g (20 mmol) of compound (IV), 8.00 g (80 mmol) of potassiumhydrogencarbonate and 40 ml of methanol were refluxed under heating forthree hours. After cooling, the reaction solution was analyzed byhigh-performance liquid chromatography and was confirmed to contain 82%of compound (III) by relative area.

INDUSTRIAL APPLICABILITY

According to the method of the present invention,2-amino-4,6-dimethoxypyrimidine useful as an intermediate for drugs andpesticides, particularly as an intermediate for pesticides (disclosed inJP-A-59-122488, JP-A-61-210084 and JP-A-60-208977), its startingmaterial 2-amino-5-chloro-4,6-dimethoxypyrimidine and its intermediate2-amino-4,5-dichloro-6-methoxypyrimidine can be easily produced, and thepresent invention is highly useful.

What is claimed is:
 1. A method for producing2-amino-4,6-dimethoxypyrimidine, comprising:reacting2-amino-5-chloro-4,6-dimethoxypyrimidine with a hydrogen donor using ametal catalyst selected from the group consisting of nickel catalyst,palladium catalyst and platinum catalyst.
 2. The method according toclaim 1, wherein the 2-amino-5-chloro-4,6-dimethoxypyrimidine isobtained by reacting 1,1,1,2,2,3,3-heptachloropropane,1,1,1,2,3,3,3-heptachloropropane or hexachloropropene with guanidine ora salt thereof, in the presence of an alkali metal hydroxide, analkaline earth metal hydroxide, an alkali metal methoxide or an alkalineearth metal methoxide.
 3. The method according to claim 1, wherein the2-amino-5-chloro-4,6-dimethoxypyrimidine is obtained by reacting2-amino-4,5-dichloro-6-methoxypyrimidine with methanol in the presenceof an alkali metal hydroxide, an alkaline earth metal hydroxide, analkali metal methoxide or an alkaline earth metal methoxide.
 4. Themethod according to claim 3, wherein the2-amino-4,5-dichloro-6-methoxypyrimidine is obtained by reacting2-amino-4,5,6-trichloropyrimidine with methanol in the presence of analkali metal carbonate, an alkali metal hydrogencarbonate, an alkalineearth metal carbonate or an alkaline earth metal hydrogencarbonate. 5.The method according to claim 1, wherein the2-amino-5-chloro-4,6-dimethoxypyrimidine is obtained by reacting2-amino-4,5,6-trichloropyrimidine with methanol in the presence of analkali metal hydroxide, an alkaline earth metal hydroxide, an alkalimetal methoxide or an alkaline earth metal mechoxide.
 6. A method forproducing 2-amino-4,6-dimethoxypyrimidine, comprising:reacting1,1,1,3,3,3-hexachloropropane or 1,1,3,3,3-pentachloropropene withguanidine or a salt thereof, in the presence of an alkali metalhydroxide, an alkaline earth metal hydroxide, an alkali metal methoxideor an alkaline earth metal methoxide.
 7. A method for producing2-amino-5-chloro-4,6-dimethoxypyrimidine, comprising:reacting1,1,1,2,2,3,3-heptachloropropane, 1,1,1,2,3,3,3-heptachloropropane orhexachloropropene with guanidine or a salt thereof, in the presence ofan alkali metal hydroxide, an alkaline earth metal hydroxide, an alkalimetal methoxide or an alkaline earth metal methoxide.
 8. The method ofclaim 1, wherein said contacting is conducted in the presence of a base.9. The method of claim 1, wherein said contacting is conducted in theabsence of a base.